The long-term goals of this project are to understand the immunobiology of asthma and allergic diseases. While our knowledge of the role of Th2 responses in the pathogenesis of asthma has improved over the past 10 years, our understanding of the mechanisms that dampen Th2 biased inflammation and that protect against the development of asthma remains rudimentary. Th1 cells may have a role in protection against asthma, however, our recent studies indicate that multiple additional mechanisms play more critical roles in regulating asthma and allergy. In this proposal we will identify and examine in detail these additional immune mechanisms that down-modulate Th2 responses, and determine the cell types and molecules that participate in the protection against Th2-biased inflammation and asthma. In Specific Aim 1 (Hypothesis 1), we will determine the mechanisms by which immunological tolerance protects against asthma and allergic disease. We will define the cellular and molecular events by which pulmonary dendritic cells mediate T cell tolerance induced by the respiratory exposure to allergen, and determine the characteristics of the regulatory cells induced by these pulmonary dendritic cells. In Specific Aim 2 (Hypothesis 2), we will determine the mechanisms by which immune deviation, involving IL-10, TGF- CD8 cells and toll-like receptor signaling, regulates asthma and allergic disease. These molecules, cytokines and cell types are activated by immunization with the adjuvant heat killed Listeria monocytogenes (HKL), a very effective stimulator of the innate immune system. We will examine the characteristics of immune responses induced with HKL, which potently down regulate airway inflammation and protect against the development of airway hyperreactivity. Finally, in Specific Aim 3 (Hypothesis 3) we will identify novel pathways involved in protection against asthma, by studying a unique congenic BALB/c mouse strain (HBA), that produces low levels of IL-4 and resists the development of airway hyperreactivity. In collaboration with Dr. Patrick Brown at Stanford, we will use gene expression profiling with cDNA microarrays to compare the specific genes and molecular pathways in BALB/c versus HBA mice, thereby developing a distinctive molecular portrait of the biology of protective immunity. These studies will greatly extend our knowledge of immune responses that protect against asthma and the Th2 biased immune responses that are pathologic for asthma and allergy. These studies therefore, are likely to lead to greatly improved therapies that protect against and potentially cure asthma and allergic diseases.